Over 28,000 thyroidectomies are performed in the United States annually for suspected malignancy. However, up to 18,000 of these are benign on permanent histology. This phenomenon is due to the fact that fine needle aspirations (FNA) of the thyroid that are suspicious for malignancy ultimately turn out to represent a benign process in 60% of cases. Because of this phenomenon we chose to examine follicular neoplasms of the thyroid for molecular markers that would distinguish a follicular adenoma from a carcinoma. Up to 40 follicular neoplasms of the thyroid were screened by microsatellite polymorphism analysis that might distinguish the two. Although there was no difference between follicular adenomas and follicular carcinomas, Hijrthle cell neoplasms of the thyroid appeared to have greater loss of heterozygosity on chromosomes 1q and 2p that could distinguish Hijrthle cell adenomas from Hijrthle cell carcinomas. These abnormalities could also be demonstrated on FNA samples with 100% sensitivity and 75% specificity; a potential dramatic improvement over what can now be accomplished by cytology. Because Hiirthle cell neoplasms of the thyroid represent a very small percentage of thyroid carcinomas that still left the clinical dilemma of distinguishing follicular adenomas from carcinomas as well as lesions that were suspicious for papillary thyroid carcinoma. We, therefore, examined follicular neoplasms and lesions that were suspicious for papillary cancer for telomerase activity. We found that 100% of follicular carcinomas and 67% of papillary thyroid cancer have a positive telomerase activity. As a result of this above work, we are prospectively collecting FNA samples from patients who have suspicious lesions on thyroid cytology. The collaborating institutions include the University of Pittsburgh and Mayo Clinic at Jacksonville. To date we have collected 127 samples and are currently examining the use of telomerase as a marker to distinguish benign from malignant. Should we be able to accomplish this and apply it to FNA then theoretically this technique could result in the obviation of up to 18,000 thyroidectomies performed annually in this country.